Photo courtesy of NIH
The gene FOXC1 is associated with aggressive acute myeloid leukemia (AML), according to research published in Cancer Cell.
Researchers said tissue-inappropriate derepression of FOXC1 has functional consequences and prognostic significance in AML.
They found evidence suggesting that FOXC1 enhances clonogenic potential, helps block monocyte/macrophage differentiation, accelerates leukemia onset in mice, and leads to inferior survival in AML patients.
“This is an important finding which helps us understand how acute myeloid leukemia develops and why some cases of AML are more aggressive than others,” said study author Tim Somervaille, MBBS, PhD, of The University of Manchester in the UK.
“Here, instead of being faulty or mutated, this normal gene is turned on in the wrong place at the wrong time, which makes the cancer grow more rapidly. There are certain situations where this gene is necessary, as in the development of the eye and skeleton before birth, but when it’s switched on in the wrong tissue, it causes more aggressive forms of leukemia.”
Dr Somervaille and his colleagues said FOXC1 is expressed in at least 20% of human AML cases but not in normal hematopoietic populations.
The researchers analyzed levels of transcription factor genes in data from published studies to identify transcription regulators expressed in human AML hematopoietic stem and progenitor cells (HSPCs) but not normal HSPCs. In these studies, FOXC1 was among the genes that were most highly upregulated in AML HSPCs.
Further investigation revealed that FOXC1 expression is associated with mutations in NPM1 and t(6;9) but no other recurring mutations in AML.
When Dr Somervaille and his colleagues conducted experiments with human AML cells, they found that FOXC1 “contributes to oncogenic potential by maintaining differentiation block and clonogenic activity.”
In vitro experiments with normal HSPCs showed that FOXC1 expression temporarily impairs myeloid differentiation. In mice, expression of FOXC1 in normal HSPCs reduced donor:recipient chimerism in the blood and skewed differentiation toward the myeloid lineage and away from the B-cell lineage.
By comparing samples from AML patients, the researchers found that FOXC1 expression is associated with high HOX gene expression.
Subsequent experiments showed that FOXC1 collaborates with HOXA9 to enhance clonogenic potential and cell-cycle progression, help block monocyte/macrophage and B-lineage differentiation, and accelerate the onset of symptomatic leukemia in mice.
To determine if the same effects occur in humans, the researchers again analyzed data from AML patients. The results indicated that FOXC1 expression helps block monocyte/macrophage differentiation and leads to inferior survival.
Dr Somervaille and his colleagues said these findings may have therapeutic implications, as previous research has shown that, in basal-like breast cancer, high FOXC1 expression renders cells more susceptible to pharmacological inhibition of NF-kB. But additional research is needed to investigate therapeutic implications for AML.
